Research Summary

Anton M. Jetten, Ph.D., is Chief of the Immunity, Inflammation, and Disease Laboratory, head of the Cell Biology Group, and holds a secondary appointment in the NIEHS Epigenetics and Stem Cell Biology Laboratory. Work performed by members of the Cell Biology Group has led to the discovery of a number of novel transcriptional regulators: several orphan nuclear receptors, nuclear receptor-associated proteins (Project I), and the GLIS proteins (Project II). Subsequent studies revealed that these proteins play critical roles in the regulation of many physiological processes (development, immunity, metabolism), are implicated in several major human pathologies (e.g., asthma, fibrosis, autoimmune disease, diabetes, autism, cancer, metabolic syndrome, cystic kidney disease), provide a link between environment and genome, and offer therapeutic potential to intervene in these illnesses.

In the last 50 years there has been a substantial increase in the incidence of chronic inflammatory disease that seems to follow the pattern of industrialization and urban living. These incidences include increases in allergic conditions, such as asthma and food allergies, autoimmune disorders (e.g., type 1 diabetes, multiple sclerosis), and metabolic syndrome. It is clear that, in addition to genetic predisposition, environmental risk factors, including endocrine disruptors and diet, play a critical role in these increases. Obesity is a major global health concern and an important theme of the NIH strategic plan .

In the United States alone, 30 percent of the general population is obese and an estimated 66 percent of all adults are overweight. Obesity is a risk factor in several pathologies, including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and asthma. There is increasing evidence for important links between the regulation of metabolism/energy homeostasis and immununological processes (immunometabolism). For example, obesity affects the immune system and promotes inflammation, while immune cells and cytokines can regulate metabolism/energy homeostasis. The RORs and TAK1/TR4 nuclear receptors regulate both immune responses and energy homeostasis/metabolism and as such might be part of the interplay between these two processes.

RORs and TAK1 nuclear receptors play an important role in the interplay between immunological and metabolic processes, mediate environment/genome interactions, and function as potential therapeutic targets.

About 12 percent of the U.S. population suffers from some form of chronic kidney disease, while 10 percent of U.S. adults have type 2 diabetes today. Due to the dramatic increase in obesity, type 2 diabetes is expected to rise over the next 40 years to as many as one in three adults. Worldwide 250 million suffer from type 2 diabetes. Type 1 diabetes increased almost two-fold over a 25-year period in many parts of the U.S. and Europe. The current annual cost related to diabetes is estimated at $174 billion. The GLI-Similar (GLIS) proteins play a critical role in the regulation of pancreas development, insulin expression, and the maintenance of kidney functions and are implicated in inflammation, fibrosis, diabetes, cancer, and cystic kidney disease. GLIS proteins might provide novel therapeutic targets for these diseases.

Jetten obtained his Ph.D. from the University of Nijmegen, The Netherlands, and completed postdoctoral studies at the Massachusetts Institute of Technology. He has published over 250 peer-reviewed journal articles and book chapters.